DESCRIPTION: Training Plan: The research and development plan will include three years of intensive laboratory work. The candidate has completed clinical training in Internal Medicine and Rheumatology, and has five years of post-doctoral research experience in cellular and molecular immunology, and now seeks funding for greater than 95% time dedicated to basic immunology research. The goal of the research project is to characterize the functional roles of the OX40 receptor (OX40R) and ligand (OX40L) molecules in T cell responses. The OX40R is a tightly regulated T cell activation antigen of the tumor necrosis factor receptor (TNFR) family, which is expressed during normal immune responses and in acute and chronic autoimmune diseases. The newly described OX40L is primarily a B cell/APC activation antigen of the TNF/Ligand family, which, when expressed in recombinant form, can transmit strong costimulatory signals for the proliferation and cytokine secretion of CD4+ T cells. The candidate hypothesizes that the OX40 R/L interaction provides important signals for immune cell activation and survival. The aims of the project are to: 1) characterize the inhibitory effects of soluble OX40R-Ig on mixed lymphocyte responses, as well as the functional and biochemical effects of OX40R signaling on T cells; 2) assess immunotherapeutic potential in an autoimmune disease model; and 3) characterize the immunologic effects of targeted disruption of the OX40L gene. These studies should help clarify the immune modulating potential of the OX40 R/L system.